Polyazamacrocyclic metal complexing agents such as the polyazamacrocycles (e.g., 1,4,7,10-tetraazacyclododecane and its derivatives, "TACD"), porphyrins (e.g., tetraphenylporphine, "TPP") and porphyrinoid compounds are of interest as both therapeutic and diagnostic agents. For example, derivatives of TACD complexed with paramagnetic metal ions have been used as contrast enhancing agents for magnetic resonance imaging (MRI) to enhance the diagnostic yield of images obtained with this technique. See, for example, Lauffer, R. B., Magn. Reson. Q. 1990:6, 2 and references therein. Metallated tetraazamacrocycles have also been used therapeutically and are particularly useful in cancer chemotherapy. See, for example, Meares, C. F., et al., Br. J. Cancer Suppl. 1990:10, 21.
Metalloporphyrins are of interest as photosensitizing agents for tumor therapy. See, for example, Jori, G., et al., J. Photochem. Photobiol. B 1990:6, 93. Additionally, porphyrins which are metallated with paramagnetic metal ions such as gadolinium (III) have been used as MRI contrast enhancing agents. For example, see Lyon, R. C., et al., Magn. Reson. Med. 1987:4, 255. The gadolinium complexes of a class of porphyrinoids or expanded porphyrins known as "texaphyrins" have proven of particular interest in imaging applications. For example, see, Young, S. W., et al., Proc. Nat. Acad. Sci. U.S.A. 1996:93, 6610 and Young, S. W., et al., Invest. Radiol. 1996:31, 280. In addition, the lutetium (III) complexes of texaphyrins are useful in photodynamic therapy applications. Woodburn, K. W., et al., J. Clin. Laser Med. Surg. 1996:14, 343; Young, S. W., et al., Photochem. Photobiol. 1996:63, 892.
The texaphyrins are aromatic pentadentate macrocyclic "expanded porphyrins" that are useful as magnetic resonance imaging (MRI) contrast agents, radiosensitizers, chemosensitizers and as agents in photodynamic therapy (PDT). As used herein, the term "expanded porphyrins" denotes a tripyrrolic pentaazaporphyrinoid compound. A texaphyrin is an aromatic benzannulene containing both 18.pi.- and 22.pi.-electron delocalization pathways. See, for example, Sessler, J. L., et al., Accounts of Chemical Research 1994:27, 43. Texaphyrins and water-soluble texaphyrins and methods of preparation have been described in U.S. Pat. Nos. 4,935,498, 5,252,720, 5,256,399, 5,272,142, 5,292,414 and 5,599,923, all of which are incorporated herein by reference.
The metal complexes of aromatic texaphyrins are produced by the oxidation and metallation of a reduced nonaromatic macrocycle precursor (the "sp.sup.3 " compound). The resulting reaction mixture contains free (uncomplexed) metal ions in solution together with the texaphyrin-metal complex product. The free metal ions must be removed from the reaction mixture because they can have a deleterious effect on biolocalization (reducing efficacy) or on stability, and they can interfere with use of the texaphyrin-metal complex in any of its various functions. More importantly, the free metal ion can render texaphyrin-metal complex preparations toxic in vivo.
In current practice, texaphyrins are metallated using a mixture of the macrocycle and a metal salt in an organic solvent such as methanol. When the metal salt is only sparingly soluble in the organic solvent, the metallation reaction is slow, the rate-limiting step being the dissolution of the metal salt. To offset the low solubility of the metal salt, it is necessary to use substantial volumes of the organic reaction solvent, a stoichiometric excess of the metal salt and long reaction times. As the reaction is scaled up, large amounts of both solvent and metal salt are required. This quickly passes from unwieldy to impractical. As the required amounts of solvent and metal salt increase, there is a need for specialized reaction vessels, the amount of chemical waste generated is increased, and purification of the metallated macrocycle becomes burdensome.
Production of large volumes of waste to produce relatively small amounts of product is undesirable due to both the expense of the starting chemicals and the expense associated with disposing of the chemical waste. Further, there is a growing sensitivity to the long-term environmental impact associated with disposal of chemical waste in landfills or by incineration. Thus, both economic and ecological concerns dictate that the amount of waste chemicals produced by a reaction sequence be minimized whenever possible.
The current reaction sequence affords yields of the desired macrocycle-metal complex which are low, often no more than 20-30% of the theoretical yield. Further, the required reaction times are lengthy (e.g., 29 h). Purification protocols must be used to remove from the reaction mixture the sparingly soluble unreacted metal salt, which is present in substantial excess, thereby increasing the time and number of steps required to isolate the desired product. Thus, a method for metallating expanded porphyrins, such as texaphyrins, which affords good yields of the desired product, after a short reaction time and a simple purification protocol would be quite desirable. If such a method could also reduce solvent and metal salt use it would constitute a substantial advance in this field. This invention provides such a method.